(1) Field of the Invention
The present invention relates to the use of groups chemically modified polysaccharides which have carboxylic acid on the eyeball. The composition provides a timed release of the medicament on the outside of the eyeball.
(2) Description of the Related Art
The prior art describes various compositions derived from natural carbohydrates for use as carriers and processes for the preparation of modified carbohydrates, particularly cellulose. Natural polymers and gums have been used in pharmaceutical formulations of sustained-release carriers, and modified celluloses, carboxy methylcellulose (CMC) and modified methyl cellulose (MMC) are found in a large number of formulations as viscosity enhancers. Because of their wide acceptance of these modified natural polymers, pharmaceutical companies are interested in the use of modified natural polymers for their drug delivery systems. Natural polymers with gelling properties that have been successfully used in topical formulations include gellan gum and carrageenans. Topical formulations with gelling properties afford increased ocular bioavailability of certain drugs.
The literature and patents show that much of the focus is centered around natural polymers. GELRITE, a registered trademark of Monsanto, is used by Merck (Radway, N.J.) in a preparation of timolol, TIMOPTIC XE. This is the only known in situ gelling drug delivery system currently on the market. It is a low-acetyl gellan gum which would have a structure similar to FIG. 3 and can ionically crosslink in the presence of a divalent cation such as calcium. Rozier et al (International Journal of Pharmaceutics 57:163-168 (1989) has shown that in in vivo testing GELRITE behaved similar to HEC (hydroxyethycellulose), a known viscosity enhancer. It significantly reduced intraocular pressure over the HEC and this was determined to be caused by an increased residence time at the surface of the eye.
Another natural gel-forming polysaccharide is alginate. Cohen et al (Opthalmic Delivery System. US, Teva Pharmaceutical Industries (1998)) describe an alginate system that gels in the presence of calcium ions in the eye. Alginate is a mixture of guluronic and mannuronic acids. They suggest using a mixture with the guluronic acid concentrations higher than 65% to form a suitable gel. When testing pilocarpine, a common glaucoma treatment, the alginate formulated system demonstrated a correlation between the gelation capability of the alginate formulation and the speed at which it occurs and the sustained release properties. It was also claimed that there was excellent ocular tolerance in the test rabbits; even though redness of the conjunctivae was reported for 1-2 hours after instillation of the drops.
A final natural polysaccharide that can form gels in situ is pectin. The pectin was isolated from Aloe Vera, which contains a higher galacturonic acid ration will form a gel when subjected to mono- or divalent ions at a low pectin of concentration of 0.25% w/v. It will also form a gel in the presence of small organic compounds, proteins, nucleic acid, and live cells.
GELFOAM, a structured matrix of gelatin, has been studied for the release of pilocarpine. The matrix is a structured water-insoluble sponge prepared from purified pork skin gelatin that will biodegrade. Because this simple matrix released most of the drug within 15 minutes, retardants had to be added. This matrix embedded in cetyl ester wax demonstrated zero-order release kinetics while the matrix impregnated with polyethylene glycol 400 monostearate exhibited close to first-order kinetics. The results show that gelatin itself does not provide for good sustained release. The following table summarizes work in ocular drug delivery systems.
TABLE 3Ocular drug delivery systemsMatrix MaterialMethod of ActionAuthorNatural PolymersAlginateIonic concentrationCohen (Cohen 1998)Gellan GumIonic concentrationRozier (Rozier, Mazuel et al.(1989)PectinIonic concentrationNI (Ni and Yates (2002)GelatinNot in situ gelationNadkarni (Hadkarni andYalkowsky (1993)CyclodextrinsNot in situ gelationSynthetic PolymersPoloxamerTemperature changeLin (Lin and Sung 2003)PluronicTemperature changeLin (Lin and Sung 2003)CarbopolpH changeLin (Lin and Sung 2003)CellulosepH changeGurney (Gurney 1986)acetophthalate
Many synthetic polymers have been tested for sustained release in the eye. While they have the advantage of being engineered to specific applications, their breakdown products are not always known, which can lead to extended FDA testing. The prior art has described a formulation approach of combining Carbopol and Pluronic. Carbopol is a high molecular weight carboxy vinyl polymer and Pluronic is a class of block copolymers containing polyoxyethylene and polyoxypropylene. This formulation claims to be free-flowing at non-physiological conditions (pH 4.0 and 25° C.), but forming a gel at physiological conditions (pH 7.4 and 37° C.). A disadvantage to this system is the high amount of Pluronic (14%) required for optimal gel formation. Again there are many disadvantages of synthetic polymers including high polymer concentration, irritancy and potentially harmful breakdown products.
Objects
It is an object of the present invention to provide modified polysaccharides for topical use on the eyeball. This and other objects will become increasingly apparent by reference to the following description.